Using molecular genetic techniques, the chief objectives of this proposal are to home in on the disease gene in X-linked bipolar affective illness and to detect other major genes in the transmission of the disorder. These goals will be attained by 1. gene mapping and related DNA techniques; and 2. conducting linkage studies with DNA markers in suitable pedigrees segregating bipolar and related affective disorders. The study will also aim to characterize linked vs. unlinked cases on clinical measures in an attempt to identify and define homogeneous subsets of the disorder and to compare different populations and ethnic groups for possible genetic differences. Long-term goals will include cloning of the defective genes; determination of their structure; searching for their biological products; and assessment o( gene-environment interaction. Israel is the data collection site. There are six main reasons for this choice: 1. X-linked pedigrees have already been identified. 2. Availability of large multigenerational pedigrees with multiple affected cases that are readily accessible for study. 3. Low rates of alcoholism and drug use, conditions that confound the psychiatric diagnosis. 4. An opportunity to compare different populations and culture. 5. Previous successful collaboration and intriguing findings that require extension. 6. The relatively low cost of human research. Israel, probably uniquely, meets all these requirements. The availability of a unique population, coupled with recent methodological advances such as molecule genetic techniques, approaches to systematically obtaining family data, structured interviews, precise diagnostic criteria with improved reliability; and a range of genetic models, holds much promise for unraveling the genetic mechanisms that underlie affective illness. This, in turn, could have major implications for the etiology, nosology, pathophysiology and, possibly, prevention and treatment of these disorders.